FDA Advisory Panel Calls for Revised Class Labeling for Menopausal Hormone Replacement Therapy

An advisory panel convened by the FDA on July 17 signaled a major shift in federal thinking about menopausal hormone therapy (HT). The panel, composed of leading clinicians and researchers in gynecology, cardiology, endocrinology, and women’s health, concluded that black box warnings on estrogen-containing therapies are outdated and not supported by current evidence. The group overwhelmingly favored removing or revising the warnings, particularly for low-dose vaginal estrogen products.

The Long Shadow of the WHI

Concerns about menopausal hormone therapy go back more than 2 decades to the 2002 publication of the Women's Health Initiative (WHI) findings in JAMA, which associated combined estrogen-progestin therapy with increased risks for cardiovascular disease, stroke, pulmonary embolism, and breast cancer. The trial was halted early due to perceived health risks and led directly to boxed warnings on systemic and vaginal estrogen products alike.

“Doctors called their patients to get off of it immediately,” FDA Commissioner and panel chairman Marty Makary, MD, said during the discussion. “The many benefits of hormone therapy were ignored... Prescriptions for hormone replacement therapy plummeted. Women flushed their pills down the toilet.”

Makary emphasized that despite the fear surrounding breast cancer, “in the 2002 paper, there was no statistically significant increase in breast cancer mortality.” He added, “As a result of the fear of breast cancer, 60 million plus women have not been offered the incredible health benefit of hormone replacement therapy."

Makary also highlighted data from the Mayo Clinic dating to the 1950s, which found women who had their ovaries removed in their 20s were at higher risk for heart attacks. “There is a powerful and profound cardioprotective effect of estrogen on the ovaries,” he said. He referred to more recent studies that have demonstrated that initiating estrogen therapy within 10 years of menopause onset is associated with a 25% to 50% reduction in fatal heart attacks and cardiovascular disease.

Are Class-Wide Warnings Valid?

Panelists agreed that the WHI’s findings do not apply to modern hormone therapy regimens, particularly low-dose vaginal estrogens and bioidentical formulations like 17β-estradiol.

“The science has evolved, but the warning labels haven’t,” said Heather Hirsch, MD, MS, NCMP, an internal medicine physician and founder of the menopause clinic at Brigham and Women's Hospital. “It’s time for the FDA’s language to catch up with the data.”

James Simon, MD, clinical professor at George Washington University and founder of IntimMedicine Specialists, criticized the class labeling that applies uniform warnings across all estrogen therapies regardless of dose or delivery. “I believe that in terms of the low-dose vaginal estrogen label, they have failed,” Simon said. He noted that the 4 µg dose of Imvexxy (estradiol vaginal insert) delivers estradiol levels similar to prasterone (Intrarosa), which carries no such warning.

JoAnn Pinkerton, MD, professor of obstetrics and gynecology at University of Virginia Health System, cited a 2025 systematic review and meta-analysis published in AJOG showing no increased risk of cancer recurrence among women with a history of breast cancer who used vaginal estrogen therapy. She also emphasized important age-dependent outcomes in the WHI. Among women aged 50 to 59, she pointed out, conjugated estrogen alone was associated with reductions in all-cause mortality, cardiovascular events, and incidence of breast cancer. “The boxed warning is not supported by science,” she said. “It reflects a class labeling which was extrapolated from [the WHI trial]. It overstates risk.”

Howard Hodis, MD, professor of cardiology at the University of Southern California Keck School of Medicine, urged regulators to rely on the full scope of existing data. “We have 50 years of data,” Hodis said. “These data should be followed. Not just the data that gives us these particular outcomes that we want to believe but look at all of the data.”

He emphasized that the only adverse outcome in the WHI with an absolute risk of 10 events per 10,000 women per year was deep vein thrombosis in the estrogen-progestin group. He also pointed out that all-cause mortality and Alzheimer disease incidence were significantly lower among women receiving estrogen alone compared with placebo.

Vaginal Estrogen Safety

The panel highlighted that safety profiles differ substantially between systemic and vaginal hormone therapies, a distinction obscured by current labeling practices.

Pinkerton emphasized the need to revise warnings on vaginal estrogen products, particularly for genitourinary syndrome of menopause. “There is an absence of a randomized clinical trial or consistent observational evidence linking vaginal estrogen for [GSM] to cancer, heart disease, dementia, blood clots or stroke,” she said.

Stephanie Faubion, MD, medical director of The Menopause Society and director of the Mayo Clinic Center for Women’s Health added, “[The boxed warning] should not be on low-dose vaginal products, as the risks are not the same.”

Orthopedic surgeon Vonda Wright, MD, drew attention to estrogen therapy’s protective effect on bone health. “Estrogen therapy reduces postmenopausal fracture risk by up to 50%—and may even lower fracture-related mortality,” she said. “Current warnings scare women and their doctors away. That’s a missed opportunity to prevent life-altering injuries and even save lives.”

Gaps in Education

Panelists repeatedly stressed that insufficient training is a critical barrier to appropriate HT use. “We’ve got a generation of women suffering in silence—feeling dismissed, confused or afraid—because of how this topic has been handled,” said FDA Principal Deputy Commissioner Sara Brenner, MD, who moderated the session.

Brigham and Women's Hospital's Hirsch added that “gaps in training magnify the damage,” and called for change starting in medical school. “Even if a clinician is not going to be the prescriber per se, if there is a clear consensus for who should or could have a consultation for HT, I do think that’s really important.”

Mary Jane Minkin, MD, clinical professor at Yale School of Medicine, echoed those concerns. She cited 2023 data showing only 31.3% of U.S. residency programs have standardized menopause curricula. “We need to start training people,” Minkin said. “The other thing that’s crucial is we have to train other practitioners. We need to train nurse practitioners, we need to train our [physician assistants], and many of them are tremendously interested in menopause care.”

Next Steps

While the panel meeting did not include a vote or formal recommendation, the FDA announced it will open a public docket in the coming weeks to collect feedback. Most panel members supported modifying the boxed warning language to reflect patient age, hormone type, and route of administration—or removing it entirely in the case of vaginal estrogen.

Faubion summarized the individualized approach many panelists endorsed: “Calculating an individual woman’s risk-benefit ratio for the use of HT involves a number of factors, including her age, time since menopause onset, estrogen plus progesterone or estrogen alone (eg, presence or absence of a uterus), cardiovascular disease and breast cancer risk factors as well as personal preferences.”

As Makary concluded, “The goal of the meeting was to separate medical dogma from evidence.”

Reference

FDA expert panel on menopause and hormone replacement therapy for women. Panel discussion. US Food and Drug Administration. Published July 17, 1015. Accessed July 24, 2025. Available at https://www.youtube.com/live/_2ZRlOivC5M.